An international team, co-led by Adriana Sánchez-Danés, principal investigator of the Cancer and Stem Cell Biology Lab at the Champalimaud Foundation, in Lisbon, has shown for the first time the important role of Survivin – a protein that has key roles in regulating cell division and inhibiting apoptosis (programmed cell death) – in the initiation and formation of a basal cell carcinoma, the most common human skin cancer. Their results have now been published in the print edition of January 8, 2025, of the journal Cell Discovery.

“Basal cell carcinoma is by far the most common skin cancer in humans”, says Sánchez-Danés. “We all know people that have had one, if not ourselves.” Basal cell carcinoma rarely metastasises, and is usually treated by simple surgery, but it can also, in some cases, become metastatic or locally very aggressive. “That's why it's so important to understand the different stages and steps that lead to the formation, as well as to the progression of this disease”, adds the researcher.

In 2016, Sánchez-Danés – also in collaboration with co-leading author of the new study Cédric Blanplain, from the Université Libre de Bruxelles – published a study in Nature showing that skin stem cells give rise to basal cell carcinoma, but not other cells called progenitor cells, which are the immediate descendants of stem cells.

This has now prompted these researchers to further analyse what is at the root of this difference in cancer initiation potential. “The new question was: what are the mechanisms that are mediating competence for cancer initiation in the stem cells but not in progenitor cells? Are there specific mechanisms in the stem cells that make them competent?”, says Sánchez-Danés.

To address this question, they performed, in animal models, a so-called transcriptional profiling of both oncogene-expressing skin stem cells and skin progenitor cells. Essentially, this consisted in comparing the genes expressed in stem and progenitor cells of the mouse skin that had their oncogenes (cancer-causing genes) activated. They were thus able to identify several genes that were upregulated (overexpressed) in the activated stem cells, and this is what put them on the track to finding… Survivin, also known as BIRC5. “Survivin was the one gene that really attracted our attention”, says Sánchez-Danés.

Unraveling the mechanisms of basal cell carcinoma initiation and progression

Interestingly, the Survivin gene is highly expressed in most human cancers, such as lung, pancreatic and breast cancers, relative to normal tissues; it is an anti-apoptotic (pro-survival) gene that plays a key role during cell division. “Next, we were keen to understand whether Survivin expression in the activated stem cells was triggering survival of the cells and increased proliferation, resulting in basal cell carcinoma”, the researcher further explains.

In order to determine whether Survivin really plays a role in basal cell carcinoma initiation – and formation – in stem cells, the team decided to delete the gene in their genetic mouse models following the activation of cancer-causing genes. They hypothesised that, if Survivin was required for tumour formation, its deletion would render the stem cells unable to generate a tumour. And that’s exactly what they saw.

The next question the team asked was: would overexpression of the Survivin gene now make progenitor cells also able to initiate a tumour? “For this, we created a new genetic mouse model that allowed us to overexpress Survivin”, says Sánchez-Danés. This effectively made progenitor cells able to make basal cell carcinoma tumours. Survivin overexpression triggered proliferation in those progenitors, and at the same time prevented apoptosis and differentiation, leading to cancer formation.

Conversely, the researchers also found that Survivin inhibition in preneoplastic lesions, using Survivin inhibitors, prevented their conversion into invasive tumours.“This showed that Survivin is required not only for the initiation and the formation of preneoplastic lesions, but also for their conversion from preneoplastic into invasive cancer”, Sánchez-Danés points out.

“Survivin has been shown to be upregulated in many human tumours, and to be important for tumour growth and maintenance. But this is the first time its role in tumour initiation is described”, Sánchez-Danés emphasises. “In addition, finding that it is required for the conversion of preneoplastic lesions into invasive tumours is relevant, as it might be exploited therapeutically.”

Therapeutic potential

Indeed, the results have potential therapeutic implications, as several Survivin inhibitors have been developed and are currently being tested in clinical trials. “Our data also show that short term administration of a Survivin inhibitor leads to shrinkage and elimination of preneoplastic lesions and prevents basal cell carcinoma progression”, the researchers write.

However, the Survivin inhibitor they used was a bit toxic for the animals. “This prompted us to find an alternative strategy”, says Sánchez-Danés. “So rather than using a Survivin inhibitor, we used an inhibitor of a protein called “serum and glucocorticoid-regulated kinase 1” (SGK1), which also prevented preneoplastic lesions from advancing into a tumour.”

Several SGK1 inhibitors have recently been developed and described to lead to tumour shrinkage alone or in combination with other treatment options in a variety of tumour types, the authors remark in their paper. “Our data show that SGK1 inhibition can prevent the conversion of preneoplastic lesions into invasive tumors, representing an alternative to the use of Survivin inhibitors in the prevention of basal cell carcinoma progression.”

Actually, both strategies could in principle be used in humans, because Survivin inhibitors could be applied as a cream on the skin, and so would have less side effects than the systemic administration of a drug, as was the case in the study with the experimental mouse models.

“Our key result is that Survivin can help us, in the future, to prevent the generation of invasive basal cell carcinomas”, says Sánchez-Danés.

“For me, the most beautiful part of our study was finding that Survivin can also induce cells that are resistant to cancer formation to become competent in this regard”, she concludes. “That’s a very strong message. We were not sure whether it would be the case when we started the project, but it turned out to be true. It was an exciting discovery.”